Abstract The opioid epidemic remains a serious national crisis, with deaths from opioid overdose skyrocketing over the last 10 years. This escalation is driven by abuse of prescription opioids and heroin, indicating that improved treatment would reduce the incidence of abuse and the risk of overdose. A multi-modal approach that includes behavioral and pharmacological interventions is most effective in treating abuse, and several pharmacotherapies, including buprenorphine, are available. Even with these treatment options, opioid abuse is not decreasing, perhaps because it is a complex problem and multiple factors must be addressed during treatment. For example, most patients are physically dependent and polydrug abusers. After proper initiation of treatment, buprenorphine can suppress withdrawal signs and decrease abuse of opioids; however, its ability to alter abuse of drugs from other pharmacological classes, such as cocaine, is limited. To better treat these complicated issues, buprenorphine could be combined with a second medication, and one drug that is receiving considerable attention is the serotonin2C (5-HT2C) receptor agonist lorcaserin. Drugs of abuse can increase extracellular dopamine; by decreasing dopamine neurotransmission, which can be accomplished indirectly using lorcaserin, abuse of a variety of drugs, including those for which there are no approved pharmacotherapies (e.g. cocaine), might be reduced. In fact, lorcaserin has been shown to decrease ongoing self-administration of cocaine, nicotine, ethanol, and opioids and to attenuate reinstatement of extinguished responding that was previously maintained by cocaine or heroin. Because lorcaserin would not be expected to suppress opioid withdrawal, it would not be adequate as a stand-alone treatment for most opioid abusers; however, a combination of buprenorphine and lorcaserin might be a novel, safe and highly effective approach for treating opioid use disorder. Proposed studies use nonhuman primates and procedures that are well established in this laboratory to provide proof of concept for using buprenorphine/lorcaserin mixtures to treat opioid abuse. In Aim 1, a self- administration procedure is used to model ongoing abuse, and in Aim 2, reinstatement of extinguished responding is used to model relapse to drug use. In both Aims, mixtures of buprenorphine and lorcaserin are expected to attenuate the effects of heroin and cocaine at dose combinations that do not alter responding for food, and these results would support the continued development of this drug combination for treating drug abuse. Importantly, these potential treatment drugs have already been approved for use in humans, and if proposed studies demonstrate therapeutic potential for this combination in monkeys, buprenorphine/lorcaserin mixtures could be evaluated in humans very soon. Meanwhile, because long-term treatment would be needed in drug abusers, future studies in monkeys would examine the chronic effects of these mixtures, including tolerance and physical dependence. These studies could lead to a novel treatment option to address the ongoing and very complicated opioid epidemic.